突触再可塑性在脊髓损伤恢复中的作用

突触可塑性是用来描述突触传递效能的一种活动依赖性变化,其长时程改变可分为长时程增强(LTP)和长时程抑制(LTD)。再可塑性是突触可塑性的一种高阶形式,即通过前呈刺激活动依赖性调节LTP或LTD的诱导或表达。关于脊髓突触可塑性及其在脊髓损伤中的作用,国内外已有较多研究报道,近年来脊髓突触再可塑性的机制研究及其对脊髓损伤恢复的影响逐渐成为热点。本文主要对突触再可塑性及其在脊髓损伤恢复中的作用研究进行综述。     

星形胶质细胞在调节突触可塑性中的作用

突触传递的可塑性被认为是学习和记忆的神经生物学基础,其取决于不同的神经元突触前和突触后机制。然而,最近有越来越多的研究涉及可塑性的第三个要素——突触周围的胶质细胞。传统观念一直认为星形胶质细胞(astrocyte,AS)仅是被动的辅助角色,起支持和营养等作用。近年的研究发现,无论在中枢还是外周神经系统,星形胶质细胞都主动参与了信息的传递与整合,并通过其释放的神经胶质递质等直接影响突触的可塑性。本文结合近年来的研究结果,对AS在突触可塑性中的研究进展作一综述。     

突触可塑性与药物成瘾

突触可塑性是指突触在形态结构和功能上的可变动性和可修饰性，包括形态结构和功能的可塑性，是大脑重塑的基础，也是学习和记忆的神经生物学基础。药物成瘾或药物依赖，是由滥用药物与大脑奖赏系统相互作用产生的慢性、复发性脑病，主要表现为强迫性用药和对药物的持续性渴求。其本质是代偿性适应。大量研究表明，突触可塑性机制广泛参与了药物成瘾的发生、发展。本文拟从突触的形态结构和功能的可塑性两方面阐述其与药物成瘾的关系。     

多巴胺转运体在精神兴奋剂依赖中的作用

精神兴奋剂是一类能够兴奋中枢和外周神经系统并容易产生依赖性的精神活性物质。大量研究表明,单胺类神经递质尤其是多巴胺在精神兴奋剂的行为效应和精神兴奋剂依赖过程中发挥重要作用,而多巴胺转运体控制着神经元内多巴胺的稳态和多巴胺神经通路的传递,因此多巴胺转运体在精神兴奋剂的奖赏和行为刺激效应中具有重要作用。     

微小RNA132在突触可塑性以及药物成瘾中的作用

复吸是药物成瘾防治的一个难题,它被认为是由于脑内正常的奖赏相关学习记忆环路被篡夺或改变而导致的病理行为。研究成瘾记忆形成和提取后突触可塑性的机制,对于寻找能够消除成瘾记忆的靶分子极为重要。已有研究显示,成瘾性药物（如可卡因）能诱导成瘾相关脑区中多种非编码微小RNA(microRNA,miRNA)表达水平的变化,而部分miRNAs也被证明可通过调控靶基因的表达参与调控突触结构可塑性。其中,非编码微小RNA 132(microRNA-132,miR-132)不仅与树突棘的形态发生、学习记忆等功能相关,也可能参与药物成瘾过程。因此,本文对miR-132调控突触可塑性的作用作一综述,以期为miR-132在药物成瘾病理性记忆方面的深入研究提供思路。     

阿片受体固有活性与阿片类物质依赖

阿片类物质依赖作用的机理仍不完全清楚，近年来学术界对阿片受体固有活性与阿片类物质作用的关系表现出很大的兴趣。阿片受体慢性暴露于阿片类物质后固有活性的变化与阿片类物质依赖产生的关系是研究阿片类成瘾机制热点问题之一。     

生长相关蛋白和突触素对突触可塑性的影响

GAP-43为生长相关蛋白,涉及轴突末梢的生长及突触结构重建。而P38则参与多种突触相关活动,与其他囊泡蛋白相互配合调节突触囊泡的停靠与融合,实现Ca2＋依赖性神经递质释放过程。最近的研究进一步证实,P38和GAP-43除作为突触结构及功能的标记物外,也参与突触可塑性发育,这些研究提示,     

阿片精神依赖和复发的神经生物学研究进展

阿片依赖是一种慢性复发性脑部疾病，阿片类物质的正性强化效应或奖赏效应是造成阿片依赖的主要原因。阿片依赖不仅涉及阿片受体作用系统本身，还与多种神经递质及受体系统的代偿性适应有关，如多巴胺、兴奋性氨基酸、5-羟色胺和促肾上腺皮质激素释放因子等神经递质及其受体系统。     

NMDA受体拮抗剂的奖赏效应与阿片类药物精神依赖性

阿片类药物的奖赏效应是阿片类药物产生精神依赖性的重要因素。多种受体及相应配体参与阿片类药物的奖赏效应。Ｎ -甲基 -Ｄ -天冬氨酸(ＮＭＤＡ )受体是谷氨酸受体的一个类型 ,越来越多的研究表明 ,ＮＭＤＡ受体参与介导多种药物的奖赏效应［２］。本文主要论述不同ＮＭＤＡ受     

阿片类物质依赖合并高血压病患者口服药物治疗效果对照观察

目的：探讨阿片类物质依赖合并高血压病患者戒毒期间临床治疗效果。方法：对216名阿片依赖合并高血压病患者和90例无吸毒史的高血压病患者均采用CCB、ACEI、利尿剂、ARB、B一受体阻滞剂5种降压药物治疗。结果：阿片依赖合并高血压病患者在用药3个月时难治性高血压比例为79．63％,药物治疗6个月后降至55．09％（P〈0．01）;平均用药数量在3个月和6个月时分别为3．30±s1．08种和2．60±s0．95种（P〈0．05）,远高于同时期无吸毒史的高血压病患者水平1．90±s0．81种和1．86±s0．73种（P〈0．01）。结论：阿片依赖合并高血压病患者用药种类和难治高血压比例均高于无吸毒史的高血压病患者,且在戒毒早期对降压药物敏感性降低。     

Ethanol modulation of synaptic plasticity

Synaptic plasticity in the most general terms represents the flexibility of neurotransmission in response to neuronal activity. Synaptic plasticity is essential both for the moment-by-moment modulation of neural activity in response to dynamic environmental cues and for long-term learning and memory formation. These temporal characteristics are served by an array of pre- and post-synaptic mechanisms that are frequently modulated by ethanol exposure. This modulation likely makes significant contributions to both alcohol abuse and dependence. In this review, I discuss the modulation of both short-term and long-term synaptic plasticity in the context of specific ethanol-sensitive cellular substrates. A general discussion of the available preclinical, animal-model based neurophysiology literature provides a comparison between results from in vitro and in vivo studies. Finally, in the context of alcohol abuse and dependence, the review proposes potential behavioral contributions by ethanol modulation of plasticity.This article is part of a Special Issue entitled ‘Synaptic Plasticity and Addiction’.     

Determinants of buprenorphine treatment for opioid dependence

This study assessed the social, demographic and clinical determinants of whether an opioid-dependent patient received buprenorphine versus an alternative therapy. A retrospective cohort analysis of opioid-dependent adults enrolled in Group Health Cooperative between January 1, 2006 and December 1, 2010 was performed. Increasing the number of physicians with DATA waivers in a region and living in a relatively-populated area increased the likelihood of being treated with buprenorphine, indicating that lack of access is a potential barrier. Comorbidity also appeared to be a factor in receipt of treatment, with the effect varying by diagnosis. Finally, patients with an insurance plan allowing health services to be sought from any provider, with increased cost sharing, were significantly more likely to receive buprenorphine, implying that patient demand is a factor. Programs integrating patient education, physician training, and support from addiction specialists would be likely facilitators of increasing access to this cost-effective treatment.     

The effect of telephonic patient support on treatment for opioid dependence: outcomes at one year follow-up

Objective

The present study examined the impact of a telephonic patient support program known as HereToHelp™ (HTH) on compliance and treatment outcomes among opioid dependent (OD) patients new to buprenorphine treatment (BUP).

Method

A total of 1426 OD patients new to BUP were randomized to receive BUP alone (standard care) or BUP plus the HTH patient support program. All patients completed the Addiction Severity Index (ASI) at the time of enrollment, and at 12 months post-enrollment.

Results

Subjects randomized to the HTH support program who accepted at least 3 care coach intervention calls were more compliant with BUP than the standard care group at month 12 (64.4% vs. 56.1%, χ² = 5.09, p < .025). Compared to patients who were non-compliant with BUP, compliant patients reported significantly lower scores on all 7 of the ASI composite scores, indicating lower severity on addiction-related problems.

Conclusions

The HTH intervention seemed to improve patient treatment outcomes indirectly by improving compliance with BUP. Supplementing BUP with a structured, telephonic compliance-enhancement program is an effective way to improve compliance with medication which then improves patient outcomes.     

The effects of ladasten on dopaminergic neurotransmission and hippocampal synaptic plasticity in rats

Derivatives of adamantane, like memantine, are potentially neuroprotective drugs for the favourable care of Alzheimer's and Parkinson's diseases. A further adamantane derivate is N-(2-adamantyl)-N-(para-bromophenyl)-amine (ladasten) which is capable to modulate animal performance in different learning paradigms. To clarify if some of those behavioural alterations are mediated by modulation of catecholamine syntheses we studied the effects of single administration of ladasten (50 mg/kg, per os) on catecholamines' biosynthesis in the ventral tegmental area, nucleus accumbens, hypothalamus, striatum and hippocampus. We found that ladasten differentially regulates tyrosine hydroxylase mRNA and protein as well as dopamine and L-DOPA content. We then investigated the effects of ladasten on activity-dependent hippocampal synaptic plasticity in vitro and found that application of 10 microM ladasten transforms short-term potentiation of synaptic transmission to a long-lasting form. A transformation of short-term into long-term potentiation was also observed, when ladasten was applied 40 min after a single 100 Hz 200 ms tetanization. This reinforcement was blocked by the protein synthesis inhibitor anisomycin and could be attenuated by the D1/D5 receptor antagonist SCH23390. These results suggest that ladasten induces reinforcement of short-term potentiation via protein synthesis and dopamine dependent mechanisms.     

注射用纳曲酮微球预防阿片类药物依赖复吸的临床研究

目的：评估注射纳曲酮微球预防阿片类药物依赖复吸的疗效和安全性。方法：筛选符合海洛因依赖且无其他躯体疾病,年龄18~45岁,至少有3次复吸史,自愿接受戒毒治疗的患者24例。随机纳入研究组及对照组,研究组注射纳曲酮微球,对照组服用盐酸纳曲酮片;疗程均为20周,停药后随访4周。在第0、2、4、8、12、16、20、24周时观察疗效和安全性。结果：研究组和对照组各纳入12名海洛因依赖患者,1名患者未参加随访,2名患者中途退出,共有21名患者（研究组11人,对照组10人）顺利完成实验。自给药后4~24周,研究组尿检阴性率均高于对照组,其差异在接受治疗后8周时有统计学意义（P =0.035）。研究组5人（45.5%）及对照组中2人（20.0%）完成全部访视。研究组与对照组的平均脱落时间分别为18.55周与11.40周,差异有统计学意义（P=0.033）。自用药后4周,研究组用药1 h后渴求评分均低于对照组,在访视5（用药后4周）和访视7（用药后12周）时有显著性差异（P=0.028;P=0.042）。在整个研究过程中,没有出现严重的治疗相关不良事件。结论：与口服纳曲酮片相比,注射用纳曲酮微球能降低患者复吸风险,减轻患者戒毒期间对毒品的渴求程度,提高患者服药依从性,增加其自愿接受治疗的时间,无不良事件发生风险,可以考虑作为海洛因依赖防复吸治疗的有效手段。     

Extended-release naltrexone for alcohol and opioid dependence: A meta-analysis of healthcare utilization studies

Through improved adherence, once-monthly injectable extended-release naltrexone (XR-NTX) may provide an advantage over other oral agents approved for alcohol and opioid dependence treatment. The objective of this study was to evaluate cost and utilization outcomes between XR-NTX and other pharmacotherapies for treatment of alcohol and opioid dependence. Published studies were identified through comprehensive search of two electronic databases. Studies were included if they compared XR-NTX to other approved medicines and reported economic and healthcare utilization outcomes in patients with opioid or alcohol dependence. We identified five observational studies comparing 1,565 patients using XR-NTX to other therapies over 6 months. Alcohol dependent XR-NTX patients had longer medication refill persistence versus acamprosate and oral naltrexone. Healthcare utilization and costs was generally lower or as low for XR-NTX-treated patients relative to other alcohol dependence agents. Opioid dependent XR-NTX patients had lower inpatient substance abuse-related utilization versus other agents and $8170 lower total cost versus methadone.     

An estimation of the prevalence of opioid dependence in New Zealand

Background

An accurate prevalence estimate for opioid dependence in New Zealand, and hence the extent of unmet treatment need, is lacking.

Methods

Opioid users were recruited via snowball sampling, with participants initially recruited from opioid substitution treatment (OST) services and dedicated needle exchanges in Auckland, Tauranga and Christchurch. Participants estimated the number of people they knew personally who were receiving OST and who were not receiving OST, but were using opioids daily or almost daily. From these estimates a multiplier of the ratio between these two groups was derived and applied to the known number receiving OST in New Zealand to arrive at the total population estimate.

Results

The mean multiplier estimate, weighted for treatment site, for 84 recruited participants was 2.015. The multiplier was higher for Christchurch. Initial recruitment source did not influence the value of the multiplier estimate. When the multiplier was applied to the known size of the New Zealand OST treatment population the total opioid dependent population was estimated to be 9142 (95% CI: 8248-10036), of whom half were not receiving OST.

Conclusion

This figure was lower than for previous less robust estimates, but still represents a substantial level of unmet need. Greater effort needs to be made to close this treatment gap.     

Effect of sildenafil on neuroinflammation and synaptic plasticity pathways in experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a chronic immuno-inflammatory disease of the central nervous system characterized by demyelination and axonal damage. Cognitive changes are common in individuals with MS since inflammatory molecules secreted by microglia interfere with the physiological mechanisms of synaptic plasticity. According to previous data, inhibition of PDE5 promotes the accumulation of cGMP, which inhibits neuroinflammation and seems to improve synaptic plasticity and memory. The present study aimed to evaluate the effect of sildenafil on the signaling pathways of neuroinflammation and synaptic plasticity in experimental autoimmune encephalomyelitis (EAE). C57BL/6 mice were divided into three experimental groups (n = 10/group): (a) Control; (b) EAE; (c) EAE + sild (25 mg/kg/21 days). Sildenafil was able to delay the onset and attenuate the severity of the clinical symptoms of EAE. The drug also reduced the infiltration of CD4+ T lymphocytes and their respective IL-17 and TNF-α cytokines. Moreover, sildenafil reduced neuroinflammation in the hippocampus (assessed by the reduction of inflammatory markers IL-1β, pIKBα and pNFkB and reactive gliosis, as well as elevating the inhibitory cytokines TGF-β and IL-10). Moreover, sildenafil induced increased levels of NeuN, BDNF and pCREB, protein kinases (PKA, PKG, and pERK) and synaptophysin, and modulated the expression of the glutamate receptors AMPA and NMDA. The present findings demonstrated that sildenafil has therapeutic potential for cognitive deficit associated with multiple sclerosis.     

Client and counselor attitudes toward the use of medications for treatment of opioid dependence

Attitudes, perceived social norms, and intentions were assessed for 376 counselors and 1,083 clients from outpatient, methadone, and residential drug treatment programs regarding four medications used to treat opiate dependence: methadone, buprenorphine, clonidine, and ibogaine. Attitudes, social norms, and intentions to use varied by treatment modality. Methadone clients and counselors had more positive attitudes toward the use of methadone, whereas their counterparts in residential and outpatient settings had neutral or negative assessments. Across modalities, attitudes, perceived social norms, and intentions toward the use of buprenorphine were relatively neutral. Assessments of clonidine and ibogaine were negative for clients and counselors in all settings. Social normative influences were dominant across settings and medications in determining counselor and client intentions to use medications, suggesting that perceptions about beliefs of peers may play a critical role in use of medications to treat opiate dependence.